A diastereocontrolled route to 10-arylpyrrolo[1,2-b ]isoquinolines

Article abstract of DOI:10.1021/jo302287v

The diastereocontrolled preparation of a series of 10-aryl-substituted pyrroloisoquinolines is achieved through a synthetic design that involves two key cyclization steps. First, the iodine(III)-mediated reaction of a series of N-benzylpentynamides leads to the generation of the 5-aroylpyrrolidinone skeletons. Finally, after reduction of the generated ketone group into the corresponding carbinol, the effect of a number of different acidic conditions was studied to assist the second cyclization step that occurs through an aromatic electrophilic substitution process. The study of the stereochemical course of this step led us to conclude that it takes place through a S _N1 mechanism with very high (>95% anti) diastereocontrol.

Full text of DOI:10.1021/jo302287v

Article
pubs.acs.org/joc
A Diastereocontrolled Route to 10-Arylpyrrolo[1,2‑b]isoquinolines
Irantzu Couto, Leticia M. Pardo, Imanol Tellitu,* and Esther Domínguez*
́
Departamento de Química Organica II, Facultad de Ciencia y Tecnología, Universidad del País Vasco−Euskal Herriko Unibertsitatea,
48940-Leioa (Bizkaia), Spain
S
* Supporting Information
ABSTRACT: The diastereocontrolled preparation of a series
of 10-aryl-substituted pyrroloisoquinolines is achieved through
a synthetic design that involves two key cyclization steps. First,
the iodine(III)-mediated reaction of a series of N-benzylpen-
tynamides leads to the generation of the 5-aroylpyrrolidinone
skeletons. Finally, after reduction of the generated ketone group into the corresponding carbinol, the effect of a number of
different acidic conditions was studied to assist the second cyclization step that occurs through an aromatic electrophilic
substitution process. The study of the stereochemical course of this step led us to conclude that it takes place through a SN1
mechanism with very high (>95% anti) diastereocontrol.
Scheme 1. PIFA-Mediated Construction of Substituted
Pyrrolidinones
1. INTRODUCTION
The preparation of isoquinoline-based heterocycles has been a
recurrent theme for synthetic organic chemists. The reason for
such attraction can probably be found in the opportunities that
this platform offers to assess novel and efficient synthetic
designs, and also in the fact that such a nitrogenated
heterocyclic framework is a fundamental core of numerous
drugs and biologically active natural products. In particular, the
pyrrolo[1,2-b]isoquinoline nucleus is present in some natural
products such as lycorine1 and the phenanthroindolizidine
alkaloids.2
the manipulation of the resulting pyrrolidinone derivative have
been of great value for the preparation of a number of different
heterocycles. For instance, different pyrrolodiazepinone and
pyrrolobenzodiazepinone derivatives have been obtained from
N-(3-aminopropyl)-, N-(2-aminomethylphenyl)-, and N-(2′-
nitrobenzyl)-substituted pyrrolidinones. Similarly, a series of
pyrrolopyrazinones has been prepared from N-(2′-aminoethyl)-
pyrrolidinones by the insertion, in both cases, of an additional
reductive amination step.11 More recently this strategy has been
applied to the construction of polyhydroxylated indolizidines.12
In this paper, therefore, our efforts to introduce this
intramolecular metal-free alkyne amidation procedure in a
synthetic design directed to the diastereocontrolled construc-
tion of 10-aryl-substituted pyrrolo[1,2-b]isoquinolines will be
disclosed.
Besides the selection of the Friedel−Crafts reaction applied
to N-arylmethylpyroglutamic acids and related substrates as one
of the most recurrent approaches to the construction of this
kind of heterocycle,3 a number of more elaborated procedures
for this task can be found in the literature. These include (a)
the lithium−iodine exchange reaction on N-(o-iodobenzyl)-
pyrrole-2-carboxamides under Parham cyclization conditions,4
(b) the intramolecular ring closure of 2-substituted isoquinoline
N-oxides,5 (c) the Cu(II) carboxylate-promoted intramolecular
carboamination reactions of variously substituted γ-alkenyl
amides,6 (d) the proper manipulation of 2-(2′-
methoxycarbonylbenzyl)pyrrolidines or 2-acetyl-3-carboxy-
1,2,3,4-tetrahydroisoquinolines,7 (e) the electroreductive intra-
molecular coupling of phthalimides with aromatic aldehydes,8
and (f) the application of the Pummerer reaction conditions to
2-substituted-N-benzylpyrrolidinones.9
Interestingly, although it can be considered a main entrance
to the construction of N-containing heterocycles, the list shown
above does not include the amination of alkynes as the source
for the synthesis of such a biologically important structural
motif. In this context, our group has demonstrated that the
intramolecular amidation of properly substituted alkynes I can
be performed in the presence of the hypervalent iodine reagent
PIFA [bis(trifluoroacetoxy)phenyliodane] to yield a series of 5-
aroyl- and 5-alkenoyl-2-pyrrolidinones of type II (see Scheme
1).10 The subtle selection of different groups (X and R in I) and
2. RESULTS AND DISCUSSION
Our retrosynthetic proposal (see Scheme 2) was conceived as
the combination of two key cyclization steps. We considered
that the target skeleton III should be obtained from IV through
an intramolecular acid-promoted Friedel−Crafts alkylation
reaction. It was also envisaged that the required hydroxy
group could be generated by reduction of the keto-carbonyl
Received: October 23, 2012
Published: December 3, 2012
© 2012 American Chemical Society
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Scheme 2. Key Retrosynthetic Disconnections for the
Pyrroloisoquinoline Skeleton
Table 1. Synthetic Details for Intermediates 5−7
% yield
a
entry
1
Ar1
Ar2
series
5
6
7
b
3,4-
(MeO)2C6H3
3,4-
(MeO)2C6H3
a
81
58 85 (68)/−
2
3
4
5
6
7
8
3,4-
Ph
b
c
d
e
f
95
99
81
51
60
84
81
41
32
57
65
79
67
77
60 (0)/90
(MeO)2C6H3
(>95)
Ph
Ph
71 (32)/72
(>95)
Ph
3,4-
(MeO)2C6H3
70 (74)/51
(>95)
4-(MeO)C6H4
3-(MeO)C6H4
2-naphthyl
Ph
Ph
73 (23)/88
(>95)
group that is developed (see II) after the I(III)-mediated
cyclization of V.
Ph
63 (10)/74
(>95)
With this plan in mind, pentynoic acid (1) was selected as
the backbone to insert on it all the elements required for the
generation of intermediate V. Thus, its transformation into
amides 3a−e (see Scheme 3) was accomplished in almost
quantitative yields, for most cases, by employing a number of
different benzylamines 2. Then, a Sonogashira coupling
reaction was selected to include activated and nonactivated
aryl groups at the terminal position of the triple bond.13 This
step required the use of a series of aryl halides 4 in combination
with Pd(0) and Cu(I) catalysts in the presence of diethylamine
to achieve pentynamides 5a−h (51−99%). When all parts of
substrates 5 were assembled, they were subjected to the PIFA-
mediated cyclization conditions. Hence, treatment with a slight
excess of PIFA in trifluoroethanol (TFEA) as solvent, followed
by aqueous basic workup, afforded a series of N-benzylpyrro-
lidinones 6a−h in moderate to good yields (32−79%).
Because the stereochemical relationships between substrates
and products can be employed as a clue to understand the
mechanistic insights of a given reaction, we were interested in
preparing pyrrolidinols 7 both in diastereochemically pure
forms and as mixtures of syn/anti isomers. Previous reports
from our group14 on the stereocontrolled reduction of related
5-alkenoylpyrrolidinones led us to anticipate that variable
mixtures of stereoisomers will be obtained, depending on the
reduction agent to be employed. In fact, under the action of
NaBH4, 5-aroylpyrrolidinones 6 gave rise to mixtures of (syn/
anti)-7 with de values ranging from 0% to 74% (see Table 1),
and contrarily the use of a sterically demanding reducing agent
such as L-selectride in THF at −78 °C yielded a series of 5-(1′-
hydroxybenzyl)pyrrolidinones 7 with an almost complete
diastereoselection.15 As the only exception, the sterically
crowded ketone group in 6a happened to be inert in the
presence of the latter reagent.
Ph
g
h
64 (48)/84
(>95)
2-thienyl
75 (40)/87
(>95)
a
Isolated yields for the reduction of 6a−h with NaBH4 and with L-
selectride. %de shown in parentheses for each case. Unaltered starting
material was completely recovered.
b
of 7i to establish a preliminary optimization process. With such
a model, no stereochemical concerns had to be contemplated
and, more importantly, the success of the reaction would be
expedited by, presumably, the generation of a highly stable bis-
benzylic carbocation. Therefore, the desired pyrrolidinol 7i was
easily prepared by addition of a slight excess of PhMgBr
solution to 5-benzoylpyrrolidinone 6b at 40 °C (see Scheme
4). With carbinol 7i in hand, and with the aim to generate the
Scheme 4. Synthesis of Pyrroloisoquinoline 8i
pyrroloisoquinoline skeleton 8i, two different acidic conditions
(H2SO4/TFA in CH2Cl2, and AlCl3 in CH2Cl2) were evaluated
and also confirmed in both cases (methods A and B).
Before subjecting the required substrates 7a−h to the acid-
catalyzed SEAr cyclization step, we considered the preparation
Encouraged by these results, the series of diastereomerically
pure carbinols 7a−h16 was subjected to the same reaction
Scheme 3. Synthesis of Pyrroloisoquinolines 8
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conditions to produce heterocycles 8a−g with variable yields
(see Table 2) and, with the only exception of 8g, almost
Table 2. Preparation of Pyrroloisoquinolines 8a−i from 7a−
a
i
method A,
% yield
method B,
% yield
method C,
% yield
method D,
% yield
entry
7
8
1
2
3
4
5
6
7
8
9
i
i
57
84
25
40
41
46
93
64
a
b
c
d
e
f
a
29
46
64
53
85
29
61
76
35
b
b
c
−
48
d
b
c
b
e
−
−
−
−
−
−
−
−
d
e
f
b
f/f′
g
30
−
b
b
g
h
g
h
−
51 (10)
i
i
i
i
h
−
−
−
a
Method A: H2SO4 (30 equiv), TFA (3 equiv), CH2Cl2, reflux, 2 h;
method B: AlCl3 (2 equiv), CH2Cl2, reflux, 1 d; method C: H2SO4 (30
equiv), HOAc, rt, overnight; method D: FeCl3·6H2O (2 equiv),
b
CH2Cl2, reflux, 1 d. Unaltered starting material was completely
c
recovered. Ester 10e was isolated in 57% yield (80% de).
d
e
Trifluoroester 9f was isolated in 11% yield (34% de). As a mixture
f
of regioisomers (87/13). Ester 10f was isolated in 83% yield (54%
de). Ester 10g was isolated in 52% yield (82% de). Diastereomeric
excess shown in parentheses. A complex mixture of compounds was
g
h
i
obtained. Trifluoro ester 9h was isolated in 7% yield (50% de) with
method A.
Figure 1. Series of pyrroloisoquinolines 8, trifluoro esters 9, and esters
10 synthesized.
complete diastereocontrol (>95% de, determined by 1H NMR)
in all cases and under all reaction conditions. To face the
inertness of carbinol 7e (entry 6), which can be easily explained
by the lack of proper activation at both aromatic rings, the
original list of reaction conditions A and B was extended to
conditions C (H2SO4, HOAc) and conditions D (FeCl3·6H2O,
CH2Cl2) and, in fact, the use of iron trichloride resulted in the
sole option. On the other hand (entry 7), the transformation of
pyrrolidinol 7f took place with a perceptible lack of
regioselectivity, leading to the formation of a nonseparable
mixture of 8f and 8f′ in a diminished yield. Once again (entry
8), application of conditions D was the only option to prepare
benzopyrroloisoquinoline 8g.17 Finally, it should be mentioned
that in those cases (substrates 7e−g) where the cyclization step
was a difficult task, the corresponding trifluoro esters 9 and
esters 10 were also obtained in variable yields (see Figure 1).
The discussion on the actual mechanism (SN2 vs SN1) for the
ring closure step leading to the isoquinoline skeleton was easily
clarified by inspection of the stereochemical composition of the
corresponding product when starting from either diastereo-
meric mixtures and diastereomerically pure samples of 7a,b,
obtained, respectively, in the reduction step with both reducing
agents (see entries 1 and 2, Table 1). The formation, in both
cases, of the same and unique stereoisomer (>95% de) led us to
consider a stepwise mechanism through the formation of a
benzylic carbocation rather than a concerted process from a
protonated alcohol (see Figure 2).
Figure 2. Alternative concerted and stepwise mechanisms for the
formation of pyrroloisoquinolines 8.
Figure 3. Suggested explanation for the stereochemical outcome in the
formation of anti-pyrroloisoquinolines 8.
In addition, the determination of the relationships between
protons located at positions 5, 10, and 10a through the
performance of a number of NOE experiments led us to assign
an anti stereochemistry for heterocycles 8a−f.18 Figure 3 shows
a possible explanation for this tendency that results from a
steric hindrance generated between the pyrrolidine nucleus and
the aryl ring (Ar2) in conformer VII. This model also explains
the absence of diastereocontrol in the formation in 8g because
of an additional interaction between the sterically demanding
naphthyl group (Ar2) and the N-benzyl group that leaves
conformer VI and VII equally disfavored.
3. CONCLUSION
In conclusion, an efficient and diastereoselective construction of
a series of 10-arylpyrroloisoquinolines has been performed in
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NMR (300 MHz, CDCl3) δ 8.02−7.99 (m, 1H), 7.89−7.80 (m, 2H),
7.57−7.40 (m, 4H), 5.89 (br s, 1H), 4.90 (d, J = 5.3, 2H), 2.58−2.38
(m, 4H), 1.93−1.92 (m, 1H); 13C NMR (300 MHz, CDCl3) δ 170.5,
133.9, 133.3, 131.4, 128.8, 128.7, 126.8, 126.6, 126.0, 125.4, 123.6,
82.9, 69.4, 41.9, 35.4, 14.9; IR (film) ν 3305, 2902, 2250, 1634; MS (M
+ 1, CI) m/z (%) 238 (100), 141 (63), 110 (14); HRMS (CI, TOF, M
+ H+) calculated for C16H15NO·H+ 238.1232, found 238.1243.
Typical Procedure A for the Sonogashira Coupling Reaction.
S yn t h e s i s o f N - ( 3 , 4 - D i m e t h o x y b e n z y l ) - 5 - ( 3, 4 -
dimethoxyphenyl)pent-4-ynamide (5a). Amide 3a (2.15 g, 8.7
mmol) was added to a stirred solution of 3,4-dimethoxybromobenzene
(4a) (1.2 mL, 8.3 mmol), Pd3(OAc)6 (37 mg, 0.16 mmol), PPh3 (174
mg, 0.66 mmol), and CuI (31.6 mg, 0.16 mmol) in pyrrolidine (8
mL). Stirring was continued for 2 h at reflux. When cooled, the entire
crude reaction mixture was diluted with CH2Cl2 and washed with
water (30 mL), saturated NH4Cl (30 mL), and brine (30 mL). The
organic layer was dried over Na2SO4 and filtered, and the solvent was
removed under vacuum. The residue was purified by column
chromatography (EtOAc) to afford amide 5a as a yellow solid that
only four steps. The synthetic design features an I(III)-
mediated alkyne amidation reaction leading to conveniently
substituted aroylpyrrolidine derivatives that, upon reduction of
the ketone group, are transformed into the corresponding
carbinols. It has been demonstrated that these substrates can be
converted into the final derivatives under a variety of acidic
conditions through a stepwise aromatic alkylation process. This
work opens an attractive alternative to the construction of
unprecedented C-10 arylated pyrroloisoquinolines.
4. EXPERIMENTAL SECTION
Typical Procedure for the Amidation Reaction. Synthesis of
N-(3,4-Dimethoxybenzyl)pent-4-ynamide (3a). A solution of 4-
pentynoic acid (1) (1 g, 8.9 mmol) in 5 mL of CH2Cl2 was added to a
magnetically stirred solution of EDC·HCl (2.6 g, 13.6 mmol) and
HOBt (1.8 g, 13.6 mmol) in 20 mL of the same solvent followed by
the addition of a solution of 3,4-dimethoxybenzylamine 2a (2.0 mL,
13.6 mmol) in 9 mL of CH2Cl2. The mixture was cooled to 0 °C, and
Et3N (1.9 mL, 13.6 mmol) was added dropwise and left to react at rt
overnight. Then, the reaction was diluted with CH2Cl2, water (25 mL)
was added, the mixture was decanted, and the organic layer was
consecutively washed with 20 mL of HCl (aq, 5%), 20 mL of a
saturated solution of aqueous NaHCO3, and 20 mL of a saturated
solution of NaCl. The organic layer was dried over Na2SO4 and
filtered, and the solvent was removed under vacuum. The resultant oil
was crystallized from Et2O to afford amide 3a as a white solid (98%):
mp 112−114 °C (Et2O); 1H NMR (300 MHz, CDCl3) δ 6.80 (s, 3H),
6.00 (s, 1H), 4.37 (d, J = 5.6, 2H), 3.85 (s, 6H), 2.53 (t, J = 6.7, 2H),
2.41 (t, J = 6.7, 2H), 1.96 (s, 1H); 13C NMR (300 MHz, CDCl3) δ
170.7, 149.1, 148.5, 130.7, 120.1, 111.3, 111.2, 83.0, 69.0, 56.0, 55.9,
43.5, 36.4, 15.0; IR (film) ν 3292, 2932, 2210, 1640; MS (M + 1, CI)
m/z (%) 248 (30), 247 (34), 151 (100); HRMS (CI, TOF, M + H+)
calculated for C14H17NO3·H+ 248.1287, found 248.1279.
1
was triturated in hexanes (81%): mp 120−122 °C (Et2O); H NMR
(300 MHz, CDCl3) δ 6.84−6.71 (m, 6H), 5.95 (s, 1H), 4.42 (d, J =
5.6, 2H), 3.87 (s, 3H), 3.84 (s, 3H), 3.83 (s, 3H), 3.81 (s, 3H), 2.78 (t,
J = 6.8, 2H), 2.51 (t, J = 6.8, 2H); 13C NMR (300 MHz, CDCl3) δ
171.0, 149.2, 149.1, 148.5, 130.7, 124.7, 120.0, 114.3, 112.1, 110.9,
86.7, 81.7, 55.9, 43.6, 35.8, 16.0; IR (film) ν 2968, 1738, 1647; MS (M
+ 1, CI) m/z (%) 384 (100), 383 (37), 218 (18), 151 (74); HRMS
(CI, TOF, M + H+) calculated for C22H25NO5·H+ 384.1811, found
384.1826.
Typical Procedure B for the Sonogashira Coupling Reaction.
Synthesis of N-(3,4-Dimethoxybenzyl)-5-phenylpent-4-yna-
mide (5b). A solution of Pd(PPh3)4 (856 mg, 0.74 mmol), CuI
(281 mg, 1.48 mmol), and iodobenzene (4b) (0.83 mL, 7.4 mmol) in
Et2NH (40 mL) was stirred at rt for 5 min. Then, a solution of the
amide 3a (2.2 g, 8.9 mmol) in THF (5.0 mL) was slowly added, and
the mixture was stirred for 4 h. The crude reaction mixture was diluted
with EtOAc, filtered, and washed with saturated NH4Cl. The aqueous
phase was extracted with EtOAc (3 × 30 mL), dried over Na2SO4, and
filtered, and the solvent was eliminated under reduced pressure. The
crude product was purified by column chromatography (EtOAc) to
afford amide 5b as a yellow solid that was triturated in hexanes (95%):
N-Benzylpent-4-ynamide (3b).19 According to the typical
procedure, amide 3b was obtained from benzylamine (2b) and 4-
pentynoic acid (1) in 98% yield as a white solid after purification by
crystallization from Et2O: mp 56−58 °C (Et2O); 1H NMR (300 MHz,
CDCl3) δ 7.49−7.23 (m, 5H), 5.91 (s, 1H), 4.47 (d, J = 5.7, 2H), 2.57
(t, J = 6.8, 2H), 2.44 (t, J = 6.8, 2H), 1.99 (t, J = 2.6, 1H); 13C NMR
(300 MHz, CDCl3) δ 170.8, 138.1, 128.7, 127.8, 127.6, 83.0, 69.4,
43.7, 35.4, 14.9; IR (film) ν 3304, 2923, 2246, 1645; MS (M + 1, CI)
m/z (%) 188 (100), 91 (26); HRMS (CI, TOF, M + H+) calculated
for C12H13NO·H+ 188.1075, found 188.1076.
1
mp 117−118 °C (hexanes); H NMR (300 MHz, CDCl3) δ 7.28−
7.24 (m, 5H), 6.84−6.70 (m, 3H), 6.00 (s, 1H), 4.42−4.40 (d, J = 5.6,
2H), 3.85 (s, 3H), 3.79 (s, 3H), 2.78 (t, J = 7.0, 2H), 2.51 (t, J = 7.0,
2H); 13C NMR (300 MHz, CDCl3) δ 170.9, 149.1, 148.4, 131.5,
130.6, 128.2, 127.9, 123.1, 120.1, 111.2, 88.3, 81.7, 55.9, 55.8, 43.6,
36.7, 16.0; IR (film) ν 2357, 1685, 1275; MS (M + 1, CI) m/z (%)
324 (65), 323 (24), 151 (100); HRMS (CI, TOF, M + H+) calculated
for C20H21NO3·H+ 324.1600, found 324.1609.
N-(4-Methoxybenzyl)pent-4-ynamide (3c). According to the
typical procedure, amide 3c was obtained from 4-methoxybenzylamine
(2c) and 4-pentynoic acid (1) in 62% yield as an orange solid after
1
purification by crystallization from Et2O: mp 87−88 °C (Et2O); H
NMR (300 MHz, CDCl3) δ 7.20 (d, J = 8.5, 2H), 6.85 (d, J = 8.5, 2H),
5.98 (s, 1H), 4.37 (d, J = 5.6, 2H), 3.79 (s, 3H), 2.54 (t, J = 6.4, 2H),
2.40 (t, J = 6.4, 2H), 1.96 (t, J = 2.5, 1H); 13C NMR (300 MHz,
CDCl3) δ 170.9, 158.9, 130.3, 129.0, 113.9, 83.0, 69.3, 55.2, 43.0, 35.1,
14.8; IR (film) ν 3296, 2932, 2252, 1642; MS (M + 1, CI) m/z (%)
218 (24), 121 (100); HRMS (CI, TOF, M + H+) calculated for
C13H15NO2·H+ 218.1181, found 218.1191.
N-Benzyl-5-phenylpent-4-ynamide (5c).21 According to the
typical procedure B, amide 5c was obtained from amide 3b and
iodobenzene (4b) in 99% as an orange solid after purification by
column chromatography (EtOAc) followed by crystallization from
1
Et2O: mp 50−53 °C (Et2O); H NMR (300 MHz, CDCl3) δ 7.66−
7.03 (m, 10H), 6.10 (s, 1H), 4.47 (d, J = 5.7, 2H), 2.81−2.76 (m, 2H),
2.53−2.49 (m, 2H); 13C NMR (300 MHz, CDCl3) δ 171.1, 138.1,
131.6, 128.7, 128.2, 127.9, 127.8, 127.5, 123.3, 88.3, 81.8, 43.7, 35.8,
16.0; IR (film) ν 1645, 2248, 1548; MS (M + 1, CI) m/z (%) 264
(100), 174 (4); HRMS (CI, TOF, M + H+) calculated for
C18H17NO·H+ 264.1388, found 264.1382.
N-(3-Methoxybenzyl)pent-4-ynamide (3d).20 According to the
typical procedure, amide 3d was obtained from 3-methoxybenzylamine
(2d) and 4-pentynoic acid (1) in 99% yield as an orange solid after
1
purification by crystallization from Et2O: mp 48−50 °C (Et2O); H
NMR (300 MHz, CDCl3) δ 7.28−7.01 (m, 1H), 6.90−6.64 (m, 3H),
4.30 (d, J = 5.7, 2H), 3.71 (s, 3H), 2.56−2.24 (m, 4H), 2.04−1.86 (m,
1H); 13C NMR (300 MHz, CDCl3) δ 171.6, 159.7, 140.0, 129.5,
119.7, 113.1, 112.5, 83.1, 69.4, 55.1, 43.2, 34.9, 14.8; IR (film) ν 3310,
2915, 2254, 1648; MS (M + 1, CI) m/z (%) 218 (100), 121 (29);
HRMS (CI, TOF, M + H+) calculated for C13H15NO2·H+ 218.1181,
found 218.1188.
N-Benzyl-5-(3,4-dimethoxyphenyl)pent-4-ynamide (5d). Ac-
cording to the typical procedure A, amide 5d was obtained from amide
3b and 3,4-dimethoxybromobenzene (4a) in 81% as a yellow solid
after purification by column chromatography (EtOAc) followed by
1
crystallization from Et2O: mp 98−101 °C (Et2O); H NMR (300
MHz, CDCl3) δ 7.26−7.23 (m, 5H), 6.90−6.74 (m, 3H), 6.06 (s, 1H),
4.48 (d, J = 5.7, 2H), 3.85 (s, 3H), 3.82 (s, 3H), 2.78 (t, J = 7.1, 2H),
2.51 (t, J = 7.1, 2H); 13C NMR (300 MHz, CDCl3) δ 171.1, 149.2,
148.5, 138.1, 128.7, 127.7, 127.5, 124.7, 115.6, 114.1, 110.9, 86.7, 81.7,
55.9, 55.9, 43.7, 35.8, 16.0; IR (film) ν 1738, 2254, 1512; MS (M + 1,
N-(2-Naphthylmethyl)pent-4-ynamide (3e). According to the
typical procedure, amide 3e was obtained from 2-naphthylamine (2e)
and 4-pentynoic acid (1) in 99% yield as a yellow solid after
purification by crystallization from Et2O: mp 128−129 °C (Et2O); 1H
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CI) m/z (%) 324 (100), 234 (24), 91 (12); HRMS (CI, TOF, M +
H+) calculated for C20H21NO3·H+ 324.1600, found 324.1614.
N-(4-Methoxybenzyl)-5-phenylpent-4-ynamide (5e). Accord-
ing to the typical procedure B, amide 5e was obtained from amide 3c
and iodobenzene (4b) in 51% as a white solid after purification by
column chromatography (EtOAc/hexanes, 1/1) followed by crystal-
lization from Et2O: mp 90−92 °C (Et2O); 1H NMR (300 MHz,
CDCl3) δ 7.31−7.28 (m, 5H), 7.20 (d, J = 8.6, 2H), 6.77 (d, J = 8.6,
2H), 6.08 (s, 1H), 4.40 (d, J = 5.5, 2H), 3.75 (s, 3H), 2.57 (t, J = 7.0,
2H), 2.49 (t, J = 7.0, 2H); 13C NMR (300 MHz, CDCl3) δ 171.2,
158.9, 131.6, 130.3, 129.1, 128.2, 127.8, 123.4, 114.0, 88.5, 81.7, 55.2,
43.1, 35.6, 16.0; IR (film) ν 1652, 2253, 1535; MS (M + 1, CI) m/z
(%) 294 (38), 121 (100); HRMS (CI, TOF, M + H+) calculated for
C19H19NO2·H+ 294.1494, found 294.1496.
N-(3-Methoxybenzyl)-5-phenylpent-4-ynamide (5f). Accord-
ing to the typical procedure B, amide 5f was obtained from amide 3d
and iodobenzene (4b) in 60% as a yellow solid after purification by
column chromatography (EtOAc/hexanes, 1/1) followed by crystal-
lization from Et2O: mp 68−69 °C (Et2O); 1H NMR (300 MHz,
CDCl3) δ 7.41−7.05 (m, 5H), 6.94−6.66 (m, 4H), 4.35 (d, J = 5.6,
2H), 3.68 (s, 3H), 2.70 (t, J = 7.1, 2H), 2.46 (t, J = 7.1, 2H); 13C NMR
(300 MHz, CDCl3) δ 171.6, 159.8, 140.1, 123.6, 131.6, 129.5, 128.2,
127.8, 119.8, 113.2, 112.7, 88.8, 81.5, 55.0, 43.4, 35.4, 16.0; IR (film) ν
1642, 2253, 1548; MS (M + 1, CI) m/z (%) 294 (100); HRMS (CI,
TOF, M + H+) calculated for C19H19NO2·H+ 294.1493, found
294.1499.
HRMS (CI, TOF, M + H+) calculated for C22H25NO6·H+ 400.1760,
found 400.1747.
5-Benzoyl-1-(3,4-dimethoxybenzyl)pyrrolidin-2-one (6b).
According to the typical procedure, pyrrolidinone 6b was obtained
from amide 5b in 41% as a brown oil after purification by column
chromatography (EtOAc): 1H NMR (300 MHz, CDCl3) δ 7.79 (d, J =
7.8, 2H), 7.60−7.41 (m, 3H), 6.71−6.64 (m, 3H), 5.12 (d, J = 14.5,
1H), 4.88−4.83 (m, 1H), 3.83−3.69 (m, 7H), 2.56−2.32 (m, 3H),
1.96−1.92 (m, 1H); 13C NMR (300 MHz, CDCl3) δ 197.1, 175.1,
149.2, 148.6, 134.2, 134.0, 128.6, 128.4, 128.1, 121.1, 111.8, 111.1,
60.3, 55.9, 55.8, 45.3, 29.7, 23.1; IR (film) ν 2937, 1690, 1593; MS (M
+ 1, CI) m/z (%) 340 (47), 234 (12), 202 (18), 151 (100); HRMS
(CI, TOF, M + H+) calculated for C20H21NO4·H+ 340.1549, found
340.1562.
5-Benzoyl-1-benzylpyrrolidin-2-one (6c).21 According to the
typical procedure, pyrrolidinone 6c was obtained from amide 5c in
32% as a brown oil after purification by column chromatography
1
(EtOAc/hexanes, 1/1): H NMR (300 MHz, CDCl3) δ 7.80 (d, J =
7.5, 2H), 7.63−7.41 (m, 3H), 7.33−6.96 (m, 5H), 5.24 (d, J = 15.0,
1H), 4.91−4.84 (m, 1H), 3.80 (d, J = 15.0, 1H), 2.56−2.26 (m, 3H),
2.08−1.86 (m, 1H); 13C NMR (300 MHz, CDCl3) δ 197.0, 175.2,
136.1, 134.2, 134.0, 129.0, 128.7, 128.5, 128.2, 127.7, 60.5, 45.4, 29.5,
23.2; IR (film) ν 3061, 1692, 1595; MS (M + 1, CI) m/z (%) 280
(100), 174 (10); HRMS (CI, TOF, M + H+) calculated for
C18H17NO2·H+ 280.1338, found 280.1330.
1-Benzyl-5-(3,4-dimethoxybenzoyl)pyrrolidin-2-one (6d).
According to the typical procedure, pyrrolidinone 6d was obtained
from amide 5d in 57% as a yellow oil after purification by column
chromatography (EtOAc): 1H NMR (300 MHz, CDCl3) δ 7.40−7.07
(m, 7H), 6.78 (d, J = 8.4, 1H), 5.16 (d, J = 14.8, 1H), 4.92−4.77 (m,
1H), 3.86 (s, 3H), 3.83 (s, 3H), 3.71 (d, J = 14.8, 1H), 2.47−2.23 (m,
3H), 1.95−1.87 (m, 1H): 13C NMR (300 MHz, CDCl3) δ 195.6,
175.3, 154.1, 149.4, 136.2, 128.7, 128.4, 127.7, 127.4, 122.8, 110.4,
110.2, 60.0, 56.1, 56.0, 45.3, 29.6, 23.5; IR (film) ν 3054, 1695, 1594;
MS (M + 1, CI) m/z (%) 340 (100), 174 (7); HRMS (CI, TOF, M +
H+) calculated for C20H21NO4·H+ 340.1549, found 340.1535.
5-Benzoyl-1-(4-methoxybenzyl)pyrrolidin-2-one (6e). Ac-
cording to the typical procedure, pyrrolidinone 6e was obtained
from amide 5e in 65% as a brown oil after purification by column
chromatography (EtOAc): 1H NMR (300 MHz, CDCl3) δ 7.78 (d, J =
7.4, 2H), 7.56−7.39 (m, 3H), 7.03 (d, J = 8.5, 2H), 6.74 (d, J = 8.5,
2H), 5.12 (d, J = 14.7, 1H), 4.88−4.84 (m, 1H), 3.67−3.70 (m, 4H),
2.55−2.21 (m, 3H), 2.07−1.77 (m, 1H); 13C NMR (300 MHz,
CDCl3) δ 197.0, 175.1, 159.2, 134.2, 134.1, 134.0, 129.9, 128.3, 128.0,
114.1, 60.4, 55.2, 44.8, 29.6, 23.1; IR (film) ν 3029, 1689, 1589; MS
(M + 1, CI) m/z (%) 310 (74), 204 (19), 202 (38), 121 (100);
HRMS (CI, TOF, M + H+) calculated for C19H19NO3·H+ 310.1443,
found 310.1447.
N-(2-Naphthylmethyl)-5-phenylpent-4-ynamide (5g). Ac-
cording to the typical procedure B, amide 5g was obtained from
amide 3e and iodobenzene (4b) in 84% as a yellow solid after
purification by column chromatography (EtOAc/hexanes, 1/1)
1
followed by crystallization from Et2O: mp 118−120 °C (Et2O); H
NMR (300 MHz, CDCl3) δ 8.01−7.77 (m, 3H), 7.50−7.24 (m, 9H),
6.27 (br s, 1H), 4.87 (d, J = 5.3, 2H), 2.74 (t, J = 7.1, 2H), 2.46 (t, J =
7.1, 2H); 13C NMR (300 MHz, CDCl3) δ 171.0, 134.6, 133.8, 133.4,
131.5, 128.8, 128.7, 128.6, 128.2, 127.8, 126.7, 126.0, 125.4, 123.5,
123.3, 88.4, 81.7, 41.8, 35.6, 16.0; IR (film) ν 2250, 1652, 1542; MS
(M + 1, CI) m/z (%) 314 (100), 141 (28); HRMS (CI, TOF, M +
H+) calculated for C22H19NO·H+ 314.1545, found 314.1552.
N-Benzyl-5-(2-thienyl)pent-4-ynamide (5h).21 According to
the typical procedure B, amide 5h was obtained from amide 3b and
2-iodothiophene (4c) in 81% as a white solid after purification by
column chromatography (EtOAc) followed by crystallization from
Et2O: mp 70−71 °C (hexanes). 1H NMR (300 MHz, CDCl3) δ 7.25−
7.15 (m, 6H), 7.06 (d, J = 3.2, 1H), 6.92−6.90 (m, 1H), 6.89 (br s,
1H), 4.38 (d, J = 5.9, 2H), 2.74−2.68 (m, 2H), 2.47−2.40 (m, 2H);
13C NMR (300 MHz, CDCl3) δ 171.0, 137.9, 131.2, 128.4, 127.4,
127.1, 126.6, 126.1, 123.3, 92.4, 74.5, 43.3, 35.0, 16.0; IR (KBr) ν
3292, 1647; MS (EI) m/z (%) 269 (M+, 38), 178 (100), 135 (23), 91
(80); HRMS (TOF) calculated for C16H15NOS 269.0874, found
269.0875.
5-Benzoyl-1-(3-methoxybenzyl)pyrrolidin-2-one (6f). Accord-
ing to the typical procedure, pyrrolidinone 6f was obtained from amide
5f in 79% as a yellow oil after purification by column chromatography
Typical Procedure for the PIFA-Mediated Cyclization
Reaction. Synthesis of 5-(3,4-Dimethoxybenzoyl)-1-(3,4-
dimethoxybenzyl)pyrrolidin-2-one (6a). A solution of alkynyla-
mide 5a (2.7 g, 7.0 mmol) in TFEA (112 mL) was stirred and cooled
to 0 °C. Then, a solution of PIFA (4.5 g, 10.5 mmol) in 20 mL of the
same solvent was added dropwise. The reaction mixture was stirred at
that temperature for 3 h. For the workup, aqueous Na2CO3 (10%) was
added and the mixture extracted with CH2Cl2 (3 × 20 mL). The
combined organic layers were washed with brine and dried over
Na2SO4, and the solvent was evaporated. Purification of the crude
product by flash chromatography (EtOAc) gave pyrrolidinone 6a as a
pure brown oil (58%): 1H NMR (300 MHz, CDCl3) δ 7.39 (d, J = 1.7,
1H), 7.27 (d, J = 1.7, 1H), 6.77 (d, J = 8.4, 1H), 6.67−6.57 (m, 3H),
5.05 (d, J = 14.5, 1H), 4.81−4.77 (m, 1H), 3.86 (s, 3H), 3.83 (s, 3H),
3.74 (s, 3H), 3.63−3.65 (m, 4H), 2.42−2.15 (m, 2H), 1.94−1.82 (m,
2H); 13C NMR (300 MHz, CDCl3) δ 195.7, 175.1, 154.0, 149.4,
149.1, 148.5, 128.5, 127.4, 122.7, 121.1, 118.1, 111.1, 110.3, 110.1,
59.8, 56.1, 56.0, 55.8, 55.7, 45.2, 29.8, 23.4; IR (film) ν 1621, 1594;
MS (M + 1, CI) m/z (%) 400 (47), 262 (17), 234 (18), 151 (100);
1
(EtOAc/hexanes, 1/1): H NMR (300 MHz, CDCl3) δ 7.75 (d, J =
7.2, 2H), 7.58−7.48 (m, 4H), 7.38 (t, J = 7.7, 1H), 7.10 (t, J = 7.7,
1H), 6.73−6.62 (m, 1H), 5.11 (d, J = 14.8, 1H), 4.95−4.79 (m, 1H),
3.87−3.61 (m, 4H), 2.47−2.18 (m, 3H), 1.97−1.79 (m, 1H); 13C
NMR (300 MHz, CDCl3) δ 196.9, 175.3, 159.8, 137.5, 134.1, 134.0,
129.8, 128.9, 128.2, 120.5, 113.8, 113.2, 60.6, 55.0, 45.3, 29.4, 23.0; IR
(film) ν 2945, 1648, 1596; MS (M + 1, CI) m/z (%) 310 (100), 204
(11); HRMS (CI, TOF, M + H+) calculated for C19H19NO3·H+
310.1443, found 310.1439.
5-Benzoyl-1-(2-naphthylmethyl)pyrrolidin-2-one (6g). Ac-
cording to the typical procedure, pyrrolidinone 6g was obtained
from amide 5g in 67% as a yellow oil after purification by column
chromatography (EtOAc/hexanes, 1/1); 1H NMR (300 MHz, CDCl3)
δ 8.09−7.12 (m, 12H), 5.76 (d, J = 14.6, 1H), 4.65−4.60 (m, 1H),
4.24 (d, J = 14.6, 1H), 2.59−2.15 (m, 3H), 1.90−1.86 (m, 1H); 13C
NMR (300 MHz, CDCl3) δ 197.2, 174.8, 134.2, 133.9, 133.8, 131.7,
131.6, 129.0, 128.9, 128.7, 128.2, 128.1, 126.9, 126.2, 125.1, 123.9,
60.3, 43.6, 29.7, 23.0; IR (film) ν 3011, 1693, 1598; MS (M + 1, CI)
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m/z (%) 330 (100), 202 (13); HRMS (CI, TOF, M + H+) calculated
for C22H19NO2·H+ 330.1494, found 330.1492.
obtained from 6d in a 13:87 ratio (70% combined yield), and as a
single diastereoisomer (51%) following procedure B. It was purified as
a yellowish oil by column chromatography (EtOAc). Data for the
1-Benzyl-5-(2-thienylcarbonyl)pyrrolidin-2-one (6h).21 Ac-
cording to the typical procedure, pyrrolidinone 6h was obtained
from amide 5h in 77% as a colorless oil after purification by column
chromatography (EtOAc): 1H NMR (300 MHz, CDCl3) δ 7.69 (d, J =
4.7, 1H), 7.54 (d, J = 3.6, 1H), 7.24−7.08 (m, 6H), 5.17 (d, J = 15.0,
1H), 4.72−4.66 (m, 1H), 3.75 (d, J = 15.0, 1H), 2.65−2.12 (m, 3H),
2.07−1.95 (m, 1H); 13C NMR (300 MHz, CDCl3) δ 190.3, 175.1,
140.8, 135.7, 134.9, 132.4, 128.6, 128.4, 128.3, 127.6, 62.2, 45.2, 29.4,
23.4; IR (film) ν 1685; MS (EI) m/z (%) 285 (M+, 1), 174 (68), 91
(100); HRMS (TOF) calculated for C16H15NO2S 285.0824, found
285.0825.
1
isomer obtained in procedure B is reported: H NMR (300 MHz,
CDCl3) δ 7.29−7.13 (m, 5H), 6.78−6.74 (m, 3H), 5.01 (d, J = 14.8,
1H), 4.66 (d, J = 5.5, 1H), 4.11 (d, J = 14.8, 1H), 3.82−3.69 (m, 7H,
H-5), 3.12 (brs, 1H), 2.10−1.70 (m, 4H); 13C NMR (300 MHz,
CDCl3) δ 176.3, 149.0, 148.7, 137.1, 133.5, 128.5, 128.1, 127.4, 118.6,
110.9, 109.3, 75.1, 61.9, 55.9, 45.7, 29.9, 21.6; IR (film) ν 3280, 1693;
MS (M + 1, CI) m/z (%) 342 (100), 324 (53), 234 (15), 135 (11);
HRMS (CI, TOF, M + H+) calculated for C20H23NO4·H+ 342.1705,
found 342.1708.
5-(1′-Hydroxybenzyl)-1-(4-methoxybenzyl)pyrrolidin-2-one
(7e). According to the typical procedure A, pyrrolidinone 7e was
obtained from 6e in a 87:64 ratio (73% combined yield), and as a
single diastereoisomer (88%) following procedure B. It was purified as
a yellowish oil by column chromatography (EtOAc). Data for the
Typical Procedure (Method A) for the Reduction of
Pyrrolidinones 6. Synthesis of 1-(3,4-Dimethoxybenzyl)-5-(1′-
hydroxy-3,4-dimethoxybenzyl)pyrrolidin-2-one (7a). Solid
NaBH4 (86 mg, 2.2 mmol) was added in one portion to a cold (0
°C) solution of pyrrolidinone 6a (600 mg, 1.5 mmol) in MeOH (15
mL). After 1 h, aq HCl (10%, 10 mL) was added and the temperature
was raised to rt. The whole mixture was extracted with CH2Cl2 (3 ×
10 mL), the combined organic layers were dried over Na2SO4, and the
solvent was evaporated. Purification of the crude product by flash
chromatography (AcOEt) afforded the diastereomeric mixture of
pyrrolidinones (syn/anti)-7a as a chromatographically pure colorless
oil in a 84:16 ratio (85% combined yield): 1H NMR (300 MHz,
CDCl3) δ 7.54−7.26 (m, 2H), 6.76−6.57 (m, 9H), 6.16 (s, 1H),
5.04−4.84 (m, 3H), 4.70 (d, J = 5.3, 1H), 4.25 (d, J = 17.0, 1H), 4.07−
3.52 (m, 27H), 2.39−1.72 (m, 8H); 13C NMR (300 MHz, CDCl3) δ
176.0, 174.2, 149.2, 149.1, 149.0, 148.4, 148.3, 148.1, 145.6, 133.2,
132.5, 132.1, 132.0, 128.5, 128.1, 124.1, 122.0, 120.6, 118.6, 111.7,
111.6, 111.2, 111.0, 109.2, 108.9, 77.2, 75.9, 61.8, 60.1, 56.1, 56.0, 55.9,
55.8, 51.9, 45.6, 30.1, 29.8, 23.7, 21.6; IR (film) 3270,1698; MS (M +
1, CI) m/z (%) 402 (77), 385 (24), 233 (11), 151 (100); HRMS (CI,
TOF, M + H+) calculated for C22H27NO6·H+ 402.1872, found
402.1871.
Typical Procedure (Method B) for the Reduction of
Pyrrolidinones 6. Synthesis of 1-(3,4-Dimethoxybenzyl)- 5-
(1′-hydroxybenzyl)pyrrolidin-2-one (7b). A solution of L-
selectride (0.6 mL, 1.0 M in THF) was added dropwise to a cold
(−78 °C) solution of pyrrolidinone 6b (110 mg, 0.3 mmol) in 3.0 mL
of the same solvent, and the stirring was continued at that temperature
for 30 min. Then, temperature was raised to rt and 2 mL of an aqueous
solution of NaOH (10%) was added. The whole mixture was extracted
with CH2Cl2 (3 × 10 mL), the combined organic layers were dried
over Na2SO4, and the solvent was evaporated. Purification of the crude
product by flash chromatography (EtOAc) gave pyrrolidinone 7b as
single diastereoisomer and as a chromatographically pure yellowish oil
(90%): 1H NMR (300 MHz, CDCl3) δ 7.20−7.15 (m, 5H), 6.70−6.65
(m, 3H), 4.90 (d, J = 14.6, 1H), 4.68 (s, 1H), 4.20−4.18 (m, 1H),
3.96−3.93 (d, J = 14.6, 1H), 3.74 (s, 4H), 3.72 (s, 3H), 1.92−1.70 (m,
3H), 1.18−1.15 (m, 1H); 13C NMR (300 MHz, CDCl3) δ 176.2,
148.9, 148.3, 141.1, 129.5, 128.3, 127.8, 126.3, 120.6, 111.6, 111.0,
75.0, 61.7, 55.8, 55.7, 45.3, 29.8, 21.4; IR (film) ν 3305, 1692; MS (M
+ 1, CI) m/z (%) 342 (67), 204 (46), 174 (77), 151 (100); HRMS
(CI, TOF, M + H+) calculated for C20H23NO4·H+ 342.1705, found
342.1710.
1
isomer obtained in procedure B is reported: H NMR (300 MHz,
CDCl3) δ 7.37−7.21 (m, 5H), 7.07 (d, J = 8.5, 2H), 6.79 (d, J = 8.5,
2H), 4.96 (d, J = 14.6, 1H), 4.73 (s, 1H), 4.14−3.96 (m, 2H), 3.72 (s,
4H), 2.01−1.60 (m, 4H); 13C NMR (300 MHz, CDCl3) δ 176.2,
158.9, 141.1, 129.6, 129.1, 128.4, 127.9, 126.4, 113.9, 75.0, 61.7, 55.2,
45.0, 29.9, 21.3; IR (film) ν 3284, 1689; MS (M + 1, CI) m/z (%) 312
(83), 294 (20), 204 (100), 174 (55); HRMS (CI, TOF, M + H+)
calculated for C19H21NO3·H+ 312.1600, found 312.1603.
5-(1′-Hydroxybenzyl)-1-(3-methoxybenzyl)pyrrolidin-2-one
(7f). According to the typical procedure A, pyrrolidinone 7f was
obtained from 6f in a 55:45 ratio (63% combined yield), and as a
single diastereoisomer (74%) following procedure B. It was purified as
a yellowish oil by column chromatography (EtOAc). Data for the
1
isomer obtained in procedure B is reported: H NMR (300 MHz,
CDCl3) δ 7.32−7.18 (m, 6H), 6.80−6.72 (m, 3H), 5.02 (d, J = 14.8,
1H), 4.73 (s, 1H), 4.11 (d, J = 14.8, 1H), 3.78−3.74 (m, 4H), 3.39
(brs, 1H), 2.07−1.75 (m, 4H); 13C NMR (300 MHz, CDCl3) δ 176.4,
159.7, 141.0, 138.6, 129.6, 128.4, 127.9, 126.4, 120.4, 113.8, 112.7,
74.9, 61.9, 55.2, 45.6, 29.8, 21.4; IR (film) ν 3274, 1694; MS (M + 1,
CI) m/z (%) 312 (100), 294 (58), 204 (37); HRMS (CI, TOF, M +
H+) calculated for C19H21NO3·H+ 312.1600, found 312.1603.
5-(1′-Hydroxybenzyl)-1-(2-naphthylmethyl)pyrrolidin-2-one
(7g). According to the typical procedure A, pyrrolidinone 7g was
obtained from 6g in a 74:26 ratio (64% combined yield), and as a
single diastereoisomer (84%) following procedure B. It was purified as
a yellowish oil by column chromatography (EtOAc). Data for the
1
isomer obtained in procedure B is reported: H NMR (300 MHz,
CDCl3) δ 8.03−7.55 (m, 3H), 7.48−7.24 (m, 9H), 5.59 (d, J = 14.9,
1H), 4.80−4.79 (m, 1H), 4.55 (d, J = 14.9, 1H), 4.33 (brs, 1H), 3.65−
3.56 (m, 1H), 1.97−1.56 (m, 4H); 13C NMR (300 MHz, CDCl3) δ
175.5, 140.6, 133.9, 132.2, 131.7, 128.8, 128.7, 128.6, 128.5, 128.4,
127.9, 126.6, 126.4, 125.9, 125.2, 123.7, 75.7, 61.4, 44.0, 29.8, 21.2; IR
(film) ν 3265, 1694; MS (M + 1, CI) m/z (%) 332 (100), 314 (25),
224(50), 141(34); HRMS (CI, TOF, M + H+) calculated for
C22H22NO2·H+ 332.1651, found 332.1648.
1-Benzyl-5-(1′-hydroxy-2-thienylmethyl)pyrrolidin-2-one
(7h). According to the typical procedure A, pyrrolidinone 7h was
obtained from 6h in a 70:30 ratio (75% combined yield), and as a
single diastereoisomer (87%) following procedure B. It was purified as
a yellowish oil by column chromatography (EtOAc). Data for the
1-Benzyl-5-(1′-hydroxybenzyl)pyrrolidin-2-one (7c). Accord-
ing to the typical procedure A, pyrrolidinone 7c was obtained from 6c
in a 34:66 ratio (71% combined yield), and as a single diastereoisomer
(72%) following procedure B. It was purified as a yellowish oil by
column chromatography (EtOAc). Data for the isomer obtained in
1
isomer obtained in procedure B is reported: H NMR (300 MHz,
CDCl3) δ 7.34−7.16 (m, 7H), 6.98−6.84 (m, 1H), 5.15−5.05 (m,
2H), 4.21 (d, J = 14.5, 1H), 3.82−3.76 (m, 1H), 3.06 (brs, 1H), 2.22−
1.83 (m, 4H); 13C NMR (300 MHz, CDCl3) δ 176.4, 144.4, 136.8,
128.6, 128.2, 127.5, 126.8, 125.0, 124.3, 70.9, 60.4, 45.5, 29.7, 20.7; IR
(film) ν 3274, 1694; MS (M + 1, CI) m/z (%) 288 (100), 151 (70);
HRMS (CI, TOF, M + H+) calculated for C16H17NO2S·H+ 288.1058,
found 288.1054.
1-(2,3-Dimethoxybenzyl)-5-(hydroxydiphenylmethyl)-
pyrrolidin-2-one (7i). A phenylmagnesium bromide solution (0.87
mL, 1.0 M in THF) was added to a solution of pyrrolidinone 6b (170
mg, 0.5 mmol) in THF (15 mL), and the temperature was raised to 40
°C. After 5 h, 4 mL of a saturated solution of NH4Cl was added and
1
procedure B is reported: H NMR (300 MHz, CDCl3) δ 7.31−7.15
(m, 10H), 5.06 (d, J = 14.7, 1H), 4.76−4.74 (m, 1H), 4.10 (d, J = 14.7,
1H), 3.75−3.71 (m, 2H), 2.02−1.33 (m, 3H), 0.96−0.85 (m, 1H); 13C
NMR (300 MHz, CDCl3) δ 176.2, 141.0, 137.0, 128.5, 128.4, 128.2,
127.9, 127.4, 126.3, 74.8, 61.8, 45.6, 29.8, 21.3; IR (film) ν 3315, 1690;
HRMS (CI, TOF, M + H+) calculated for C18H19NO2·H+ 282.1416,
found 282.1410.
1-Benzyl-5-(1′-hydroxy-3,4-dimethoxybenzyl)pyrrolidin-2-
one (7d). According to the typical procedure A, pyrrolidinone 7d was
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the whole mixture was extracted with CH2Cl2 (3 × 10 mL). The
combined organic layers were dried over Na2SO4 and filtered, and the
solvent was evaporated. Purification of the crude product by flash
chromatography (EtOAc) gave pyrrolidinone 7i (49%) as an orange
chromatographically pure solid that was triturated in hexanes: mp 90−
93 °C (hexanes); 1H NMR (300 MHz, CDCl3) δ 7.40−7.25 (m, 10H,
Harom), 6.77 (d, J = 8.4, 1H), 6.47−6.41 (m, 2H), 4.87 (d, J = 15.0,
1H), 4.60 (s, 1H), 3.88−3.81 (m, 7H), 3.20 (d, J = 15.0, 1H), 2.20−
2.15 (m, 1H), 2.04−1.99 (m, 3H); 13C NMR (300 MHz, CDCl3) δ
178.1, 148.9, 148.3, 145.4, 144.8, 128.5, 127.1, 125.9, 125.8, 119.9,
111.1, 80.1, 63.4, 55.9, 55.9, 45.4, 30.2, 22.9; IR (film) ν 3391, 2938,
1671; MS (M + 1, CI) m/z (%) 418 (100), 400 (27), 280 (15), 250
(43); HRMS (CI, TOF, M + H+) calculated for C26H27NO4·H+
418.2018, found 418.2034.
Typical Procedures (A−D) for the Synthesis of Pyrroloiso-
quinolinones 8. Method A. H2SO4 (aq 2 M, 30 equiv) was added to
a solution of pyrrolidinone 7 in CH2Cl2. TFA (3 equiv) was then
added, and the solution was stirred at reflux for 2 h. For the workup,
after cooling, NaOH (aq, 2%) was added and the mixture was
extracted with CH2Cl2. The organic extracts were dried with Na2SO4
and filtered, and all volatiles were removed. Purification of the crude
product by flash chromatography (EtOAc) afforded pyrroloisoquino-
lines 8a,b,d,i (see Table 2). All these compounds were obtained as oils.
Method B. Aluminum(III) chloride hexahydrate (2 equiv) was
added in one portion to a solution of pyrrolidinone 7 in CH2Cl2. After
being stirred at reflux for 24 h, the reaction mixture was cooled,
quenched with saturated aq K2CO3 solution, and then extracted with
CH2Cl2. The organic extracts were dried with Na2SO4 and filtered, and
all volatiles were removed. Purification of the crude product by flash
chromatography (EtOAc) afforded the pyrroloisoquinolines 8a−d,f,f′,i
(see Table 2). All these compounds were obtained as oils.
4.43 (d, J = 17.7, 1H), 3.97−3.66 (m, 2H), 2.59−2.34 (m, 2H), 2.16−
1.67 (m, 2H); 13C NMR (300 MHz, CDCl3) δ 174.6, 139.9, 137.5,
131.7, 129.5, 129.0, 128.9, 127.4, 126.8, 126.7, 126.3, 59.9, 52.6, 42.7,
29.8, 23.7; IR (film) ν 2942, 1679; MS (M + 1, CI) m/z (%) 264
(100), 263 (5); HRMS (CI, TOF, M + H+) calculated for
C18H17NO·H+ 264.1388, found 264.1387.
(10R*,10aS*)-10-(3,4-Dimethoxyphenyl)-1,5,10,10a-
tetrahydropyrrolo[1,2-b]isoquinolin-3(2H)-one (8d). 1H NMR
(300 MHz, CDCl3) δ 7.26−7.16 (m, 3H), 7.07−6.62 (m, 4H), 5.03
(d, J = 17.5, 1H), 4.39 (d, J = 17.5, 1H), 3.88−3.67 (m, 8H), 2.47−
2.40 (m, 2H), 2.07−1.76 (m, 2H); 13C NMR (300 MHz, CDCl3) δ
174.0, 149.2, 148.3, 137.6, 132.2, 131.7, 128.9, 126.7 126.6, 126.2,
126.8, 112.0, 111.3, 59.7, 55.9, 55.8, 52.2, 42.6, 29.7, 23.7; IR (film) ν
2944, 1684; MS (M + 1, CI) m/z (%) 324 (100), 323 (8); HRMS (CI,
TOF, M + H+) calculated for C20H21NO3·H+ 324.1600, found
324.1607.
(10R*,10aS*)-8-Methoxy-10-phenyl-1,5,10,10a-
tetrahydropyrrolo[1,2-b]isoquinolin-3(2H)-one (8e). 1H NMR
(300 MHz, CDCl3) δ 7.38−7.16 (m, 4H), 6.95−6.91 (m, 1H), 6.74−
6.57 (m, 3H), 5.02 (d, J = 17.5, 1H), 4.37 (d, J = 17.5, 1H), 3.87−3.69
(m, 5H), 2.53−2.33 (m, 2H), 2.06−1.99 (m, 1H), 1.82−1.72 (m, 1H);
13C NMR (300 MHz, CDCl3) δ 174.2, 158.3, 140.3, 133.1, 130.2,
129.7, 129.5, 128.8, 127.3, 113.0, 110.7, 60.2, 55.3, 52.0, 42.8, 29.8,
23.6; IR (film) ν 2940, 1686; MS (M + 1, CI) m/z (%) 294 (100), 293
(12); HRMS (CI, TOF, M + H+) calculated for C19H19NO2·H+
294.1494, found 294.1508.
(10R*,10aS*)-7-Methoxy-10-phenyl-1,5,10,10a-
tetrahydropyrrolo[1,2-b]isoquinolin-3(2H)-one (8f) and
( 1 0R * , 10 aS *) - 9 - M e th o x y- 1 0 -p h e n y l -1 , 5 , 1 0 , 1 0 a -
tetrahydropyrrolo[1,2-b]isoquinolin-3(2H)-one (8f′). 1H NMR
(300 MHz, CDCl3) δ 7.40−6.75 (m, 14H), 6.57−6.56 (m, 1H), 6.23−
6.22 (m, 1H), 5.19−4.96 (m, 2H), 4.39−3.60 (m, 12H), 2.52−1.69
(m, 8H,); 13C NMR (300 MHz, CDCl3) δ 174.8, 174.2, 158.3, 158.2,
139.8, 139.7, 138.9, 137.9, 124.0, 123.5, 129.5, 129.3, 128.9, 128.1,
127.5, 127.3, 127.1, 126.4, 114.6, 114.4, 114.0, 112.6, 59.8, 57.1, 55.2,
55.1, 52.8, 49.9, 42.2, 42.1, 29.9, 29.7, 23.8, 21.1; IR (film) ν 2940,
1675; MS (M + 1, CI) m/z (%) 294 (100), 293 (13); HRMS (CI,
TOF, M + H+) calculated for C19H19NO2·H+ 294.1494, found
294.1501.
Method C. H2SO4 (concd, 30 equiv) was added to a solution of
pyrrolidinone 7 in HOAc (10 mL), and the mixture was stirred
overnight at room temperature. For the workup, NH4OH was added
at 0 °C and the mixture was extracted with CH2Cl2. The organic
extracts were dried with Na2SO4 and filtered, and all volatiles were
removed. Purification of the crude product by flash chromatography
(EtOAc) afforded pyrroloisoquinolines 8a−d (see Table 2). All these
compounds were obtained as oils.
(10R*,10aR*) and (10S*,10aS*)-12-Phenyl-10,11,11a,12-
tetrahydrobenzo[f ]pyrrolo[1,2-b]isoquinolin-9(7H)-one (8g).
1H NMR (300 MHz, CDCl3) δ 8.01−6.82 (m, 22H), 5.65 (d, J =
Method D. Iron(III) chloride hexahydrate (2 equiv) was added in
one portion to a solution of pyrrolidinone 7 in CH2Cl2. After being
stirred at reflux for 24 h, the reaction mixture was cooled, quenched
with saturated aq K2CO3 solution, and then extracted with EtOAc.
The organic extracts were dried with Na2SO4 and filtered, and all
volatiles were removed. Purification of the crude product by flash
chromatography (EtOAc) afforded the pyrroloisoquinolines 8a−e,g
(see Table 2). All these compounds were obtained as oils.
(10R*,10aS*)-10-(3,4-Dimethoxyphenyl)-7,8-dimethoxy-
1,5,10,10a-tetrahydropyrrolo[1,2-b]isoquinolin-3(2H)-one (8a).
1H NMR (300 MHz, CDCl3) δ 6.89−6.50 (m, 2H), 6.64 (m, 2H),
6.22 (s, 1H), 4.97 (d, J = 16.3, 1H), 4.33 (d, J = 16.3, 1H), 3.94−3.46
(m, 14H), 2.49−2.47 (m, 2H), 2.41−2.04 (m, 2H); 13C NMR (300
MHz, CDCl3) δ 174.2, 149.2, 148.3, 148.1, 147.7, 132.5, 129.5, 124.1,
122.1, 111.9, 111.8, 111.2, 108.6, 60.1, 56.0, 55.9, 55.8, 55.7, 55.6, 42.4,
29.8, 23.7; IR (film) ν 2937, 1739; MS (M + 1, CI) m/z (%) 384
(100), 383 (13); HRMS (CI, TOF, M + H+) calculated for
C22H25NO5·H+ 384.1811, found 384.1810
(10R*,10aS*)-7,8-Dimethoxy-10-phenyl-1,5,10,10a-
tetrahydropyrrolo[1,2-b]isoquinolin-3(2H)-one (8b). 1H NMR
(300 MHz, CDCl3) δ 7.57−7.04 (m, 5H), 6.63 (s, 1H), 6.14 (s, 1H),
4.98 (d, J = 17.1, 1H), 4.33 (d, J = 17.1, 1H), 4.06−3.44 (m, 8H),
2.50−2.40 (m, 2H), 2.20−1.60 (m, 2H); 13C NMR (300 MHz,
CDCl3) δ 174.2, 148.1, 147.7, 140.2, 129.5, 129.4, 128.8, 127.5, 124.1,
111.9, 108.6, 60.1, 55.9, 55.7, 52.1, 42.4, 29.8, 23.6; IR (film) ν 2937,
1683; MS (M + 1, CI) m/z (%) 324 (100), 323 (13); HRMS (CI,
TOF, M + H+) calculated for C20H21NO3·H+ 324.1600, found
324.1609.
17.7, 1H), 5.53 (d, J = 17.7, 1H), 4.79−4.72 (m, 2H), 4.28−3.93 (m,
4H), 2.57−1.24 (m, 8H); 13C NMR (300 MHz, CDCl3) δ 174.9,
174.4, 140.6, 139.3, 134.4, 134.1, 132.5, 132.0, 131.8, 130.2, 130.0,
129.8, 129.6, 128.9, 128.7, 128.5, 128.4, 127.7, 127.4, 127.3, 127.1,
126.9, 126.8, 126.6, 126.5, 126.0, 125.9, 125.4, 122.3, 60.0, 57.0, 52.9,
50.0, 41.0, 40.9, 29.9, 29.7, 23.6, 21.0; IR (film) ν 2934, 1681; HRMS
(CI, TOF, M + H+) calculated for C22H19NO·H+ 314.1544, found
314.1539.
(
)-7,8-Dimethoxy-10,10-diphenyl-1,2,10, 10a-
tetrahydropyrrolo[1,2-b]isoquinolin-3(5H)-one (8i). 1H NMR
(300 MHz, CDCl3) δ 7.44−7.19 (m, 9H), 6.78−6.76 (m, 1H), 6.47−
6.40 (m, 2H), 4.86 (d, J = 15.0, 1H), 4.62−4.59 (m, 1H), 3.97 (s, 3H),
3.82 (s, 3H), 3.11 (d, J = 15.0, 1H), 2.30−2.19 (m, 3H), 2.02−2.00
(m, 1H); 13C NMR (300 MHz, CDCl3) δ 178.0, 148.9, 148.2, 145.1,
144.4, 129.3, 128.5, 128.4, 128.3, 127.3, 127.2, 125.9, 119.9, 111.0,
80.1, 63.3, 55.9, 55.8, 45.5, 30.0, 22.8; IR (film) ν 1737 (CO); MS (M
+ 1, CI) m/z (%) 400 (18), 250 (24), 151 (28); HRMS (CI, TOF, M
+ H+) calculated for C26H25NO3·H+ 400.1913, found 400.1921.
During the cyclization assays, acetylated (method C) or
trifluoroacetylated (method A) byproducts were detected and isolated
in variable yields (see Table 2). All these compounds were obtained as
oils.
(R*,R*) and (R*,S*)-1-(3-Methoxybenzyl)-5-(1′-
trifluoroacetoxybenzyl)pyrrolidin-2-one (9f). 1H NMR (300
MHz, CDCl3) δ 7.40−6.78 (m, 18H), 6.10 (d, J = 2.6, 1H), 5.90
(d, J = 6.3, 1H), 5.17−5.06 (m, 2H), 4.13−3.79 (m, 4H), 3.56 (s, 3H),
2.33−1.84 (m, 8H); 13C NMR (300 MHz, CDCl3) δ 175.6, 175.4,
(10R*,10aS*)-10-Phenyl-1,5,10,10a-tetrahydropyrrolo[1,2-
b]isoquinolin-3(2H)-one (8c). 1H NMR (300 MHz, CDCl3) δ
7.38−7.06 (m, 8H), 6.71−6.69 (d, J = 7.7, 1H), 5.04 (d, J = 17.7, 1H),
2
157.9 (q, JCF = 43.2, COCF3 maj,), 160.0, 159.9, 137.8, 137.6, 134.2,
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134.1, 130.0, 129.9, 129.8, 129.7, 129.2, 129.1, 126.6, 125.9, 120.4,
120.3, 113.7, 113.6, 113.5, 113.4, 115.6 (q, J = 293.1, COCF3maj),
80.6, 78.2, 60.4, 59.2, 55.2, 55.1, 45.9, 45.0, 29.4, 29.2, 21.3, 19.1; IR
(film) ν 1792, 1698; MS (M + 1, CI) m/z (%) 408 (100), 294 (52),
204 (16); HRMS (CI, TOF, M + H+) calculated for C21H20F3NO4·H+
408.1378, found 408.1418.
Science (CTQ2010-20703 and a predoctoral fellowship to I.C.)
is gratefully acknowledged.
1
REFERENCES
■
(1) Hoshino, O. In The Alkaloids; Cordell, G. A., Ed.; Academic: San
Diego; 1998; Vol. 51, pp 324−424.
(R*,R*) and (R*,S*)-1-Benzyl-5-(1′-trifluoroacetoxy-1′-thio-
phen-2-yl-methyl)pyrrolidin-2-one (9h). 1H NMR (300 MHz,
CDCl3) δ 7.39−7.24 (m, 14H), 7.06−7.01 (m, 2H), 6.30 (d, J = 2.1,
1H), 6.19 (d, J = 6.2, 1H), 5.17−5.09 (m, 2H), 4.20−4.11 (m, 2H),
3.95−3.93 (m, 2H), 2.93−1.91 (m, 8H); 13C NMR (300 MHz,
CDCl3) δ 176.0, 163.9 (q, 2JCF = 43.3, COCF3maj), 136.1, 136.0, 135.4,
135.0, 128.9, 128.1, 128.0, 127.9, 127.8, 127.5, 127.2, 127.0, 116 (q, 1J
= 287.1 (COCF3maj), 75.6, 75.2, 59.9, 59.2, 45.9, 45.2, 29.3, 29.1, 21.1,
20.0; IR (film) ν 1787, 1695; MS (M + 1, CI) m/z (%) 384 (62), 270
(100), 269 (14), 174 (19), 114 (19); HRMS (CI, TOF, M + H+)
calculated for C18H16F3NO3S·H+ 384.0881, found 384.0858.
5-(1′-Acetoxybenzyl)-1-(4-methoxybenzyl)pyrrolidin-2-one
(2) For reviews, see: (a) Li, Z.; Jin, Z.; Huang, R. Synthesis 2001,
2365−2378. (b) Michael, J. P. Nat. Prod. Rep. 2003, 20, 458−475.
(3) The generation of a number of 5-aryl-substituted pyrroloisoqui-
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Hen
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́ ́ ́
(c) Akue-Gedu, R.; Couturier, D.; Henichart, J.-P.; Rigo, B.; Sanz, G.;
Van Hijfte, L.; Bourry, A. Tetrahedron 2012, 68, 5644−5654.
(4) Ruiz, J.; Ardeo, A.; Ignacio, R.; Sotomayor, N.; Lete, E.
Tetrahedron 2005, 61, 3311−3324.
1
(10e). Reported data for the major diastereoisomer: H NMR (300
(5) Landa, A.; Minkkila, A.; Blay, G.; Jørgensen, K. A. Chem.Eur. J.
̈
MHz, CDCl3) δ 7.35−7.14 (m, 6H), 6.75−6.64 (m, 3H), 5.88 (d, J =
5.2, 1H), 5.09 (d, J = 14.6, 1H), 4.13−3.66 (m, 5H), 2.35−2.22 (m,
1H), 2.02 (s, 3H), 1.87−1.70 (m, 3H); 13C NMR (300 MHz, CDCl3)
δ 175.6, 169.6, 159.1, 136.2, 129.5, 128.6, 128.5, 126.5, 114.0, 75.3,
59.4, 55.3, 45.0, 29.5, 21.2, 21.1; IR (film) ν 1743, 1688; MS (M + 1,
CI) m/z (%) 354 (95), 294 (100), 204 (23), 174 (34), 121 (51);
HRMS (CI, TOF, M + H+) calculated for C21H23NO4·H+ 354.1705,
found 354.1694.
(R*,R*) and (R*,S*)-5-(1′-Acetoxybenzyl)-1-(3-
methoxybenzyl)pyrrolidin-2-one (10f). 1H NMR (300 MHz,
CDCl3) δ 7.36−6.75 (m, 18H, Harom), 6.11 (d, J = 2.5, 1H), 5.85 (d,
J = 2.5, 1H), 5.16−5.06 (m, 2H), 4.05−3.69 (m, 10H), 2.33−2.02 (m,
8H), 1.87−1.80 (m, 6H); 13C NMR (300 MHz, CDCl3) δ 176.4,
176.3, 175.3, 175.2, 173.4, 169.6, 1, 159.9, 158.5, 137.9, 136.2, 129.8,
129.7, 128.6, 128.5, 128.2, 128.1, 126.5, 125.8, 120.4, 120.2, 113.7,
113.5, 113.2, 113.1, 75.5, 73.1, 60.4, 59.8, 55.2, 55.1, 45.7, 44.6, 30.0,
29.4, 21.2, 18.8, 20.9, 20.7; IR (film) ν 1790, 1684; MS (M + 1, CI)
m/z (%) 354 (93), 294 (100), 204 (25), 174 (31), 121 (54); HRMS
(CI, TOF, M + H+) calculated for C21H23NO4·H+ 354.1705, found
354.1696
2006, 12, 3472−3483.
(6) Fuller, P. H.; Chemler, S. R. Org. Lett. 2007, 9, 5477−5480.
(7) (a) Brenzovich, W. E., Jr.; Benitez, D.; Lackner, A. D.; Shunatona,
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(c) Chaniyara, R.; Kapuriya, N.; Dong, H.; Lee, P.-C.; Suman, S.;
Marvania, B.; Chou, T.-C.; Lee, T.-C.; Kakadiya, R.; Shah, A.; Su, T.-L.
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9860.
(9) Islas-Jac
Tetrahedron Lett. 2011, 52, 5245−5248.
́
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́
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(10) (a) Serna, S.; Tellitu, I.; Domínguez, E.; Moreno, I.; SanMartin,
R. Org. Lett. 2005, 7, 3073−3076. (b) Tellitu, I.; Serna, S.; Herrero, M.
T.; Moreno, I.; Domínguez, E.; SanMartin, R. J. Org. Chem. 2007, 72,
1526−1529.
(11) (a) Pardo, L. M.; Tellitu, I.; Domínguez, E. Tetrahedron 2010,
66, 5811−5818. (b) Pardo, L. M.; Tellitu, I.; Domínguez, E. Synthesis
2010, 971−978.
(12) (a) Pardo, L. M.; Tellitu, I.; Domínguez, E. Synlett 2012, 881−
884. (b) Pardo, L. M.; Tellitu, I.; Domínguez, E. Tetrahedron 2012, 68,
3692−3700.
(13) The presence of deactivated aryl rings at the terminal position of
the triple bond is not compatible with the PIFA-assisted alkyne
amidation reaction. See ref 10a.
1-Benzyl-5-[1′-acetoxy-(2-naphthylmethyl)]pyrrolidin-2-one
1
(10g). Reported data for the major diastereoisomer: H NMR (300
MHz, CDCl3) δ 8.04−7.01 (m, 12H), 5.93 (d, J = 5.6, 1H), 5.69 (d, J
= 14.8, 1H), 4.57 (d, J = 14.8, 1H), 3.71−3.67 (m, 1H), 2.18−1.77 (m,
7H); 13C NMR (300 MHz, CDCl3) δ 175.7, 169.5, 136.3, 133.9,
131.6, 131.4, 129.6, 128.8, 128.7, 128.6, 128.5, 127.3, 126.7, 126.0,
125.3, 123.6, 75.3, 59.6, 44.0, 29.6, 21.1, 21.0 (CH3); IR (film) ν 1794,
1686; MS (M + 1, CI) m/z (%) 374 (8), 342 (18), 315 (18), 314
(100); HRMS (CI, TOF, M + H+) calculated for C24H23NO3·H+
374.1756, found 374.1747.
(14) See ref 12.
(15) An extensive spectroscopic study to identify the relative
stereochemical relationships at both stereogenic centers was carried
out only on the final heterocycles 8.
(16) As diastereomerically pure starting materials except for 7a.
(17) This derivative comprises the basic skeleton of an alkaloid
isolated from the aerial parts of Cynanchum komarovii that shows
inhibitory activity against the tobacco mosaic virus. An, T.-Y.; Huang,
R.-q.; Yang, Z.; Zhang, D.-k.; Li, G.-r.; Yao, Y.-c.; Gao, J. Phytochemistry
2001, 58, 1267−1269.
ASSOCIATED CONTENT
■
S
* Supporting Information
1H NMR and 13C NMR spectra for all new compounds 3, 5−
10. This material is available free of charge via the Internet at
http://pubs.acs.org.
(18) The absence of nuclear Overhauser effect between protons H-10
and H-10a clearly suggests anti stereochemistry, which was also
supported by the positive effect that was found, respectively, between
these two protons and one of each proton, H-5a or H-5b.
(19) Spectroscopic data match with those previously reported:
Jacobi, P. A.; Guo, J.; Rajeswari, S.; Zheng, W. J. Org. Chem. 1997, 62,
2907−2916.
AUTHOR INFORMATION
Corresponding Author
*E-mail: imanol.tellitu@ehu.es (I.T.); esther.dominguez@ehu.
es (E.D.).
■
Notes
The authors declare no competing financial interest.
(20) Koseki, Y.; Kusano, S.; Ichi, D.; Yoshida, K.; Nagasaka, T.
Tetrahedron 2000, 56, 8855−8865.
ACKNOWLEDGMENTS
■
(21) Previously reported by our group. See ref 10b.
Financial support from the University of the Basque Country
(UFI 11/22 and a postdoctoral fellowship to L.M.P.), the
Basque Government (GIU IT 370-10 and SAIOTEK S-
PE11UN006), and the Spanish Ministry of Education and
11199
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